Abstract 17383: Transplantation of Anti-microRNA-377-modified Bone Marrow-derived Progenitor Cells Attenuates Myocardial Infarction-induced Lv Dysfunction in Mouse

Abstract

Cardiac diseases are the predominant cause of human mortality in the United States and around the world. MicroRNAs (miRNA/miR) are small non-coding RNAs that have been shown to modulate a wide range of biological functions under various pathophysiological conditions. MiRNA act as molecular switches of gene expression and are thought to regulate complex cardiac signaling and transcriptional circuits during cardiac development and disease. However, its effects on endothelial progenitor cells (EPC) biology and function, particularly in the context of cell-based therapy for cardiomyopathy are not fully understood. The purpose of this study was to determine the miRNA profile of EPCs in response to chronic inflammatory stimuli and evaluate if miRNA-377 impairs differentiation and function of mouse bone marrow-derived EPCs after transplantation in myocardial ischemic conditions. MiRNA array profile of EPCs in response to inflammatory stimuli (LPS, 20ng/ml) for 12 hrs, EPC migration and invitro vascular tube formation was analyzed. GFP-labeled EPC (transfected with either anti-miR-377 or control-anti-miR) were transplanted intramyocardially after induction of MI in mice. miRNA array data from EPCs in response to inflammatory stimuli has indicated modulation of number of miRNAs related to angiogenesis with a robust decrease in miR-377. Pre-miR-377 transfection in EPCs inhibits their migration P<0.05) and vascular tube formation ability (P<0.05). Furthermore, EPCs treated with miR-377 mimic showed decrease in protein expression of HAND2. Interestingly, in a relevant mouse model of myocardial infarction (MI), intramyocardial transplantation of miR-377-silenced (anti-miR-377 transfected, GFP-labeled) EPCs promote neovascularization (at 28 days, post-MI) leading to improvement in myocardial repair (reduced fibrosis and infarct size). Echocardiography showed LV function was significantly improved in mice receiving miR-377-silenced EPCs compared to control-miR-transfected EPCs. Taken together, these data suggest that inhibiting miR-377 in EPCs might promote their engraftment and angiogenic ability after transplantation into ischemic myocardial tissue, possibly through activation of HAND2 signaling axes.